Several specific ophthalmic conditions are known colloquially and collectively as "dry eye." These conditions are more properly termed "tear deficiencies" or "tear film abnormalities" [Michael Lemp, Ch. 14 "Diagnosis and Treatment of Tear Deficiencies" in Duane and Jaeger's "Clinical Ophthalmology" (New York: Harper & Row, 1980)].
When the tear deficiency is largely due to a decrease in the aqueous component of the lacrimal fluid, as opposed to the outer lipid or inner mucin components, it is known as keratoconjunctivitis sicca (KCS). When KCS is associated with systemic problems, the condition is often referred to as Sjogren Syndrome. There are many other causes of dry eye, however, among which are severe inflammation, alkali burn, and the like.
There are also dry eye syndromes associated with aging, with prolonged use of contact lenses, or with environmental extremes, in which rapid tearfilm loss through evaporation becomes increasingly severe with increasing heat, wind velocity, exposure to tobacco smoke and other wind-borne particulate matter, etc.
The terms "dry eye applications," "relief of minor irritation" and "relief of redness of the eye" are used herein in their broadest sense.
Medicaments have been administered to the eye in eyedrops, ointments or creams, in gelatin lamellae or other biologically soluble or insoluble films or sheets, by dispensing ocular inserts, and as suspensions or emulsions in aqueous and non-aqueous vehicles. Certain of these dosage forms have also been used to administer ophthalmic formulations for the relief of dry eye or redness of the eye due to minor eye irritations. The disadvantages associated with many of these ophthalmic medicament delivery systems are well known. Conventional eyedrops in the form of aqueous solutions or suspensions are rapidly washed away by the eye's tear fluid or drain spontaneously away through the nasalacrimal duct. Ointments or creams blur the vision, and also have comparatively short residence times in the eye. Gelatin lamellae or other films or sheets, ocular inserts and non-aqueous suspensions and emulsions all can cause immediate pain and continuing discomfort and can also interfere with vision.
Highly viscous aqueous gels formed from carboxy vinyl polymers, such as those disclosed (but not even as dry eye formulations) in Schoenwald et al. U.S. Pat. Nos. 4,271,143 and 4,407,792, issued June 2, 1981 and Oct. 4, 1983, respectively, are difficult to administer so as to provide consistent, accurate dosages and may be uncomfortable to administer as well. Indeed, above a viscosity of about 30,000 cps, reliable administration in drop form is at best difficult to achieve and at worst impossible.
Schoenwald et al. U.S. Pat. No. 4,820,737, issued Apr. 11, 1989, discloses tear stimulant compositions of a much lower viscosity, i.e., from about 4 to 100 cps, containing, for example, N-cyclohexyl-N-methyl-2-phenylethylamine and an ophthalmically acceptable carrier which can include a viscolyzer such as hydroxyethylcellulose, hydroxpropyl methylcellulose, methylcellulose or a polyacrylamide.
UK Patent Application No. GB 2007091A (Toko) describes ophthalmic drug-containing, carboxy vinyl polymer based gels, cross-linked with a polyalkenyl polyether, over a wider viscosity range, namely 1,000 to 100,000 cps. Tear replenishment is among the contemplated uses. The relatively low viscosity preparations having viscosities of 1,000 to 10,000 are stated to have good flowability and to be amenable to application by drops directly into the mucous membrane around the eyeball. However, the use of sodium chloride in the preparation is recommended in Toko for sustained efficiency because sodium chloride is said to delay breakdown of the gel when the compositions are applied to the mucous membrane of the eye. But, the sodium chloride is also said to convert the gel to a liquid with a great reduction in viscosity. Therefore, when sodium chloride is added to the composition, increased polymer amounts are recommended to compensate for such viscosity reduction due to the addition of sodium chloride.
Robinson, U.S. Pat. No. 4,615,697, issued Oct. 7, 1986, discloses a controlled release treatment based on a bioadhesive which is described as a water-swellable, although water insoluble, fibrous, cross-linked carboxyfunctional polymer with a plurality of repeating units in which about at least 80 percent thereof contain at least one carboxy functionality and a crosslinking agent (0.05 to 1.5 percent) that is substantially free of polyalkenyl polyether. It is noteworthy that whereas Robinson seeks to exclude the use of polyalkanyl polyether crosslinkers (as are present in Carbapol 934), Toko finds Carbapol 934 especially useful. Robinson discloses the use of a polymer sized to pass through a 100 mesh sieve screen with fluorometholone; but it does not disclose or teach use as a moisturizing agent in a dry eye formulation, particularly as set forth hereafter.
An article by Liebowitz et al. in Ophthalmology, 91, No. 10 (October 1984), pp. 1199-1204, reports on experiments on treating dry eye conditions with a high viscosity gel material said to be: "a clear, semisolid formulation of synthetic, high molecular weight, cross-linked polymers of acrylic acid"; p. 1199; obtained from Alcon Laboratories, Inc., the assignee of the Schoenwald et al. patents. The other constituents of this gel, if any, are not identified, although a commentator whose remarks accompany the article speculates that water could be present; p. 1204.
Several polymeric dry eye formulations, including the commercially available Vidisic.RTM. gel dry eye formulation (Dr. Mann Pharma, Berlin, Germany) are described in two articles by Marquardt and Marquardt et al. that appeared in Klin. Mbl. Augenheilk., 189 (1986) at pp. 51-54 and 254-257, respectively. Vidisic.RTM. gel contains polyacrylic acid, MW about 4 million, physiological salt solution, sorbitol and a preservative. Other dry eye formulations described in these articles, which did not contain acrylic acid polymers, were said to contain methylcellulose and its derivatives, e.g., hydroxyethylcellulose, or polyvinyl alcohol and polyvinylpyrrolidone.
Although some of the foregoing ophthalmic formulations can be acceptable for some purposes in connection with the control of dry eye, they can be unacceptable for other purposes. For example, problems of ease and reliability of administration, comfort and/or sustained efficacy can be encountered. Also, in formulations based on prescription drugs, ease of access can present a problem.